Risk of Opioid Overdose Associated With Concomitant Use of Oxycodone and Selective Serotonin Reuptake Inhibitors

Yunusa, Ismaeel; Gagne, Joshua J.; Yoshida, Kazuki; Bykov, Katsiaryna

doi:10.1001/jamanetworkopen.2022.0194

Cited by 11 publications

(7 citation statements)

References 53 publications

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“…An additional recent retrospective analysis with similar limitations and the potential for unmeasured confounding variables found that use of SSRIs that inhibit oxycodone metabolism (paroxetine or fluoxetine; inhibit CYP2D6) at the time of oxycodone initiation was associated with a small but significantly higher risk of opioid overdose compared with the use of other SSRIs. 38 The results from this clinical trial confirmed that paroxetine caused a relatively small increase in oxycodone concentration; however, quetiapine, which inhibits CYP3A4, also increased oxycodone plasma concentration without affecting the primary outcome.…”

Section: Discussionsupporting

confidence: 56%

Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia

Florian

Schrier

Gershuny

et al. 2022

JAMA

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ImportanceOpioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects.ObjectiveTo study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia.Design, Setting, and ParticipantsRandomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021.InterventionsOxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo.Main Outcomes and MeasuresVentilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary).ResultsAmong 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], −4.9 L/min [1-sided 97.5% CI, −∞ to −0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, −10.2 L/min [1-sided 97.5% CI, –∞ to –6.3]; P &lt; .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, −1.2 L/min [1-sided 97.5% CI, −∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, −0.6 L/min [1-sided 97.5% CI, −∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, −9.3 L/min [1-sided 97.5% CI, −∞ to −3.9]; P &lt; .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, −∞ to 6.4]; P = .67). No drug-related serious adverse events were reported.Conclusions and RelevanceIn this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT04310579

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Section: Discussionsupporting

confidence: 56%

Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia

Florian

Schrier

Gershuny

et al. 2022

JAMA

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“…More specifically, paroxetine and fluoxetine are potent inhibitors of liver enzymes CYP2D6. 61 Yunusa et al 62 found that initiating oxycodone in patients on fluoxetine or paroxetine was associated with a slight increased risk of opioid overdose. On the contrary, our study found that opioid + SSRI/SNRI had significantly lower doses of opioids compared with opioid + BZD/Z-hypnotics group.…”

Section: Discussionmentioning

confidence: 99%

Co-prescribing of Central Nervous System–Active Medications for COPD Patients: Impact on Emergency Room Visits and Hospitalization

et al. 2022

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Background: Anxiety and chronic pain are common comorbidities in patients with chronic obstructive pulmonary disease (COPD), which are frequently managed with benzodiazepines (BZDs) and opioids, respectively. Objective: The purpose of this study was to determine whether different combinations of opioids, BZD, and their substitutes—gabapentinoids (GABA) and selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs)—are associated with lower risk of acute respiratory events in COPD patients with co-occurring chronic pain and anxiety. Methods: This retrospective cohort study used a nationally representative sample of Medicare beneficiaries with COPD, chronic pain, and anxiety. Patients were grouped based on drug combination (opioid + BZD/Z-hypnotics, opioid + GABA, opioid + SSRI/SNRI, BZD/Z-hypnotics + GABA, BZD/Z-hypnotics + SSRI/SNRI, GABA + SSRI/SNRI, or ≥3 drugs). The primary outcome was emergency room (ER) visit or hospitalization due to acute respiratory events assessed up to 180 days following initiation of drug combination. Overdose secondary to central nervous system (CNS)–related drugs was also assessed up to 180 days following initiation of drug combination. Results: The drug combination opioid + GABA was associated with decreased risk for ER visit (hazard ratio [HR] = 0.73; 95% CI = 0.61-0.87) and hospitalization (HR = 0.69; 95% CI = 0.55-0.85). Opioid + SSRI/SNRI also showed decreased risk for ER visit (HR = 0.84; 95% CI = 0.71-0.99). There was no significant difference in risk for CNS-related drug overdose among different drug combinations compared with opioid + BZD/Z-hypnotics. Conclusion and Relevance: Opioids in combination with GABA and SSRI/SNRI demonstrate relatively lower risk for acute respiratory events among patients with COPD and comorbid chronic pain and anxiety. The findings emphasize the need for multimodal management in this vulnerable population.

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“…4 Initiating oxycodone in patients on fluoxetine or paroxetine can increase risk of opioid overdose. 5 On the contrary, we found that the drug combination opioid + SSRI/ SNRI required significantly lower doses of opioids relative to opioid + BZD/Z-hypnotics group. A multimodal approach may lower the odds of adverse respiratory events in this vulnerable population.…”

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confidence: 54%

Author’s Reply “Considerations Regarding a Cohort Study on Concomitant Use of Central Nervous System-Active Medications in Patients With COPD”

Sood¹,

Kuo²,

Sharma³

et al. 2022

Ann Pharmacother

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Risk of Opioid Overdose Associated With Concomitant Use of Oxycodone and Selective Serotonin Reuptake Inhibitors

Cited by 11 publications

References 53 publications

Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia

Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia

Co-prescribing of Central Nervous System–Active Medications for COPD Patients: Impact on Emergency Room Visits and Hospitalization

Author’s Reply “Considerations Regarding a Cohort Study on Concomitant Use of Central Nervous System-Active Medications in Patients With COPD”

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